Perioperative Propranolol in Robotic Assisted Laparoscopic Prostatectomy- A Feasibility Study of Propranolol to Target Perioperative Stress Induced Cancer Progression
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- The feasibility of conducting a formal larger RCT to compare the efficacy of propranolol vs placebo to decrease PCa recurrence following RALP.
研究概览
简要总结
The purpose of this study is to assess the feasibility of conducting a larger randomized controlled trial to assess the efficacy of perioperative propranolol capsules compared with placebo capsules in decreasing recurrence of prostate cancer (PCa) after robotic assisted laparoscopic prostatectomy (RALP) in participants with intermediate to high-risk for prostate cancer recurrence.
详细描述
PCa is the most commonly diagnosed cancer in Norway (2020) and RALP is the most frequent curative treatment offered to men with non-metastatic PCa. Biochemical recurrence (BCR) is estimated to occur to 40% of patients with EAU IR and HR PCa. Attempts to combat the high recurrence rates after RALP with neoadjuvant treatment, aiming to reduce the local tumor burden and treat possible micrometastasis, has of yet not proven beneficial.
The prostate is highly innervated and recent evidence has shown the importance of nerves in the development and progression of PCa. The action of particularly adrenergic nerves, in sum lead to a pro-cancerous and metastatic state by influencing key hallmarks of cancer like apoptosis resistance, angiogenesis, immune suppression, invasiveness and metastasis.
Perioperative stress caused by the cancer surgery, in this case RALP, has been found to promote cancer progression and recurrence both by enhancing growth of preexisting residual tumor/micrometastasis and facilitating formation of new metastasis. The surgical stress response cause a catecholamine-induced cancer progression where β2-adrenergic receptor (ADRB2) have a key role.
Our newly published pharma co-epidemiologic study indicate perioperative stress can be targeted by a non-selective ß-blocker (nsBB) like propranolol [1]. RCTs have found perioperative administration of propranolol alone, or in conjunction with COX-2 inhibition, to be safe and to reduce biomarkers associated with poor prognosis compared with the control group receiving placebo medication in patients undergoing radical surgery for breast-, ovarian- and colorectal cancer [2-7}.
The result of our register study, together with existing evidence of an effect of propranolol/nsBBs, provides foundation for PeP-RALP, a pilot study to establish the recruitment- and infrastructure feasibility of a double-blinded, placebo controlled RCT. The results of this pilot study will be used to investigate the feasibility of a formal larger RCT aiming to assess efficacy of perioperative propranolol to reduce PCa recurrence and progression after RALP.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 40 Years 至 80 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •European Association of Urology Intermediate- and High Risk for Biochemical recurrence and planned for curative RALP
- •ECOG Performance Status 0-1
排除标准
- •Medical Conditions
- •Sick sinus syndrome
- •Atrioventricular (AV) block grade 2 and 3
- •Recent (3 months) myocardial infarction
- •Known unstable- or vasospastic- angina
- •Heart failure (New York Heart Association [NYHA] > 2)
- •Symptomatic peripheral vascular disease (e.g. intermittent claudication)
- •Known pulmonary hypertension
- •Known carotid artery stenosis or recent (3 months) stroke
- •Bronchial asthma or other chronic obstructive pulmonary disease (COPD)
- •Kidney failure (estimated Glomerular filtration rate [eGFR]<50)
- •Liver failure (cirrhosis, jaundice, signs of hepatic decompression)
- •Unregulated diabetes mellitus
- •Untreated thyroid disorder
- •Depressive episode within last 6 months (within last 12 months if major depressive episode)
- •Known drug allergy against propranolol or excipients
- •Any medical conditions considered to prohibit Propranolol use as judged by the treating physician (including frailty).
- •Participants with known substance- or alcohol-abuse
- •Prior/Concomitant Therapy
- •Recent (<3 month) use of systemic beta-blockers prior to screening.
- •Patients receiving non-dihydropyridine calcium channel blocking agents (eg diltiazem, verapamil)
- •Patients receiving anti-arrhythmic agents (e.g. amiodarone, sotalol, digoxin, verapamil, flecainide)
- •Patients receiving digoxin, rizatriptan, hydralazine, fluvoksamin, or fluoksetin
- •Patients using daily anxiolytics (e.g. benzodiazepines), alpha-receptor adrenergic agonists (e.g. clonidine)
- •Recommendations in the Summary of Product Characteristics for propranolol regarding concomitant use of other medications will be adhered to.
- •Diagnostic assessments
- •Sinus bradycardia (<60 beats/minute)
- •Resting blood pressure <110/60mmHg OR hypertension BP >160/100
- •AV-block 2 or 3 on ECG
研究组 & 干预措施
Propranolol
Participants will receive Propranolol capsule for a period of 22-28 days, low dose (1 capsule/20mg propranolol twice daily) treatment the first- and last- three days of the treatment period. Higher dose (2 capsules/40mg propranolol twice daily) for the rest of the treatment period.
干预措施: Propranolol (Drug)
Placebo
Participants will receive Propranolol capsule for a period of 22-28 days, low dose (1 capsule twice daily) treatment the first- and last- three days of the treatment period. Higher dose (2 capsules twice daily) for the rest of the treatment period.
干预措施: Propranolol (Drug)
结局指标
主要结局
The feasibility of conducting a formal larger RCT to compare the efficacy of propranolol vs placebo to decrease PCa recurrence following RALP.
时间窗: The total duration of study participation from screening to end of follow-up is 50-102 days per participant. The primary outcome will be assessed when inclusion is completed, or if inclusion is not completed within 12 months.
Numbers of eligible participants needed to screen to include 40 patients in the study, reported as % of eligible participants that subsequently were included in the study. Compliance of study intervention (defined as \>80% of doses taken). Reported as % of participants compliant to the study intervention before RALP and % of participants compliant to the study intervention after RALP.
次要结局
- Determine the effect of preoperative propranolol treatment on the serum level of PSA(7-14 days)
- To determine the effect of propranolol on post-operative biochemical failure(Up to 9 weeks)
- Surgical complications(Up to 9 weeks)
- Intraoperative anesthesiological and surgical challenges Surgical complications in PeP RALP patients(1 day)
- Safety and tolerability of PeP-RALP intervention(9 weeks)
- Determine the effect of RALP on catecholamine levels(Up to 5 weeks)
- Determine the bioavailability of propranolol(Up to 5 weeks)
研究者
Shivanthe Sivanesan
Urologist and General Surgeon
Oslo University Hospital